PROJECT SUMMARY Inflammatory bowel disease (IBD) is a major group of inflammatory conditions of the colon and small intestine and about 1-1.3 million people in the United States suffer from IBD. Crohn's disease and ulcerative colitis are the two clinically distinct, principal types of IBD - the former happens in any part of the gastrointestinal track from mouth to anus whereas the latter primarily affects the colon and the rectum. While the exact cause of IBD is not fully understood, hereditary, genetics, and environmental factors contribute to the disease development. Currently, there is no cure for IBD and remission may not be possible or prolonged. Standard of care includes surgery and medications. Acute treatment uses medications to treat infection (by antibiotics) and reduce inflammation (by aminosalicylate anti- inflammatory drugs or corticosteroids). Immunomodulators and anti-inflammation antibodies are the latest therapies for IBD patients who don't respond well to conventional therapy. However, due to serious side effects, non-specific immune suppressors including corticosteroids are not used for long- term treatment. Thus, new therapy is urgently needed for better treatment of IBD. Recently, we have discovered novel small-molecule chemical agents capable of selectively inhibiting over-development of pro-inflammatory Th17 cells in mice, but not other T-helper subsets that have different immune functions. Th17 cells have been recently recognized as a major driving factor for the pathogenesis of IBD. In this project, we will validate the therapeutic potential of our new Th17 immunomodulators as more effective and safer treatment for chronic inflammatory disorders such as IBD. We will accomplish two Specific Aims in the Phase I of this project, which are to develop highly potent and selective inhibitors that block Th17 cell development. The Phase I results will prepare us for a more efficient Phase II study of an extensive pre-clinical evaluation of our most promising drug candidates in future human clinical trials.